Levoleucovorin salts, in particular levoleucovorin calcium, are drug substances containing 5-formyl-(6S)-tetrahydrofolate or levofolinic acid.
The administration of levoleucovorin is useful as an antidote to drugs which act as folic acid antagonists and as dihydrofolate reductase inhibitors. Levoleucovorin is used as well in combination chemotherapy with 5-FU in the treatment of patients with e.g. metastatic colorectal cancer. In cancer chemotherapy typically levoleucovorin is administered intravenously in 5 to 10 mg levofolinic acid per ml aqueous solution. Stability of these aqueous solutions is limited due to oxidative degradation which yields almost insoluble degradation compounds and thus precipitates. More importantly, levoleucovorin and specifically its calcium salt have a low solubility in water and tend to form supersaturated solutions which are likely to form precipitates during storage. Therefore aqueous solutions are unstable and may form precipitates during handling and storage. The appearance of such precipitates in drug products intended for intravenous administration constitutes “Particulate Matter”, a critical quality defect and a significant risk for patients resulting in a recall of the affected drug products. Oxidative degradation of levoleucovorin is minimized if the initial solution is freeze-dried under nitrogen blanket and packaged in vials as a lyophilized powder. The product is then reconstituted before use with a diluent (e.g. water for injection, 0.9% sodium chloride or 5% dextrose solution). However, limited solubility restricts the preparation of high strength compositions, for the “ready-to-use solution” as well as the reconstituted “lyophilized powder” form. In view of these stability issues, many of the levoleucovorin containing drug products are used as reconstituted solutions made from “lyophilized powder”. There are “ready-to-use” solutions on the market which require a strict cold chain control during the entire distribution cycle (e.g. transport, warehouse, storage). The shelf life of the drug products is directly related to the degree of oxidative degradation of the drug substance, and to precipitation of less soluble degradation products. The limited aqueous solubility and possibility of precipitation dictates the limited concentration of the drug substance in the formulation and reconstituted solution. The principle reasons for the formation of particulate matter are: the crystallization of the drug substance in the supersaturated solution, and the degradation of the drug substance forming less soluble compounds which precipitate, both resulting in particulate matter.
US 2007/0099866 proposes a stable pharmaceutical composition of 5,10-methylene-tetrahydrofolate with citrate formulated in a pH range between 7.5 and 10.5. The formulations are particularly suitable for producing lyophilization solutions and lyophilizates or dry powders and dry mixtures. The lyophilizates must be reconstituted by adding suitable diluents to prepare for intravenous administration. An aqueous preparation for injection is disclosed in EP 1 640 008 consisting of 5-formyl-(6S)-tetrahydrofolic acid with a basification material or a buffer agent and an antioxidant, for example ascorbic acid. U.S. Pat. No. 4,931,441 discloses an aqueous leucovorin calcium (5-formyl-(6R,S)-tetrahydrofolic acid, calcium salt) solution in the amount of 6.35 mg per ml of solution (5 mg per ml as the free acid). The low concentration of the solution reduces the benefit of the medication during administration. A stable, injectable aqueous composition comprising a salt of folic acid or leucovorin is described in EP 0 416 232. The compound benzyl alcohol is required to preserve and stabilize the composition.
For therapeutic use such pharmaceutical compositions comprise a therapeutically effective amount sufficient for the treatment of patients. As indicated herein, it is important in the preparation of aqueous injectable solutions, that these drug products are made available to the patient in a stable high strength form without the risk of particulate matter formation. According to the instant invention, compositions as defined in the independent claim 1 have been developed to meet such requirements. Preferred embodiments are subject to the dependent claims.
The term “drug product” as used herein means a finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.
The term “drug substance” or “active pharmaceutical ingredient (API)” as used herein means an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body.
The term “stable” as used herein means that the solution comprising the reduced folates does not form any precipitates and/or crystals over a prolonged period of time, that is, over a period of time of e.g., three years. Stability thus refers to the stability of the solution to remain free of particulate matter over the entire period of their shelf live. Further details on the stability of drug products are found in “Guidance for Industry”, Q1A (R2) “Stability Testing of New Drug Substances and Products” (November 2003), section 2.2, in particular 2.2.5 “Specification” and 2.2.7 “General Case”. For the determination of particulate matter a Microscopic Particle Count Test as described in Particulate Matter in Injections, United States Pharmacopeial Convention, Revision Bulletin, Official Jul. 1, 2012 may be used.
The term “high strength” as used herein refers to solutions comprising at least 7 mg/ml of levoleucovorin (calculated as free acid).